Glycopeptide antibacterial compounds, compositions containing same and methods of using same

Abstract

The present invention relates to vancomycin analogs in which the vancosamine residue is substituted with a lipid-like substituent that includes a first aryl moiety and a second aryl moiety joined together by a flexible linker moiety, that is not a single bond directly joining the first aryl moiety and the second aryl moiety, and a glucose C-6 substituent modified to be other than the naturally occurring hydroxyl group, or pharmaceutically acceptable salts thereof.

What is claimed is:  
     
       1. A vancomycin analog whose glucose C-6 position is modified to bear a polar substituent other than a naturally occurring hydroxyl group and whose vancosamine is substituted at the amine nitrogen with a lipophilic substituent having at least a first aryl moiety and second aryl moiety joined together by a first flexible linker moiety that is not a single bond, directly joining the first aryl moiety and the second aryl moiety or a pharmaceutically acceptable salt thereof. 
     
     
       2. The analog of  claim 1  in which a second flexible linker moiety, the same as or different from the first, joins the amine nitrogen of the vancosamine and the first aryl moiety of the lipid-like substituent. 
     
     
       3. The analog of  claim 1  in which the lipid-like substituent falls within the scope of the formula K—Ar 1 —Z—Ar 2 , in which Ar 1  and Ar 2  represent a first aryl moiety and a second aryl moiety, respectively, and K and Z represent a second flexible linker moiety and a first flexible linker moiety, respectively, provided that Z is not a single bond joining Ar 1  and Ar 2 . 
     
     
       4. The analog of  claim 1  in which the lipid-like substituent comprises a benzyloxybenzyl group. 
     
     
       5. The analog of  claim 4  in which said benzyloxybenzyl group is further substituted by one or more halide groups. 
     
     
       6. The analog of  claim 1  in which the polar substituent is a free amine. 
     
     
       7. The analog of  claim 1  in which the polar substituent is a substituted amine that provides for a primary or secondary amine at a distal position. 
     
     
       8. The analog of  claim 1  in which the polar substituent is charged at or about physiological pH. 
     
     
       9. The analog of  claim 3  having the Formula I, below:                    
       in which the group K—Ar 1 —Z—Ar 2  is as described above and R is a group which has the formula:                    
       in which the groups R 3  and R 4  may be the same or different and selected from the group consisting of H, alkyl, aryl, heterocyclic, aralkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl, aminocarbonyl, substituted aminocarbonyl, substituted oxycarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl, substituted aminosulfonyl, amidino, or substituted amidino, said alkyl, aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, or heterocycliccarbonyl being optionally substituted with 1-3 groups of R 1 ; and wherein R 3  and R 4  may be linked to one another or to one or both of the others by one or more covalent bonds to form one or more aryl or heterocyclic rings of 3-20 members, optionally comprised of C, N, O, or S, provided that Z is not a single bond directly joining Ar 1  and Ar 2 . 
     
     
       10. The analog of  claim 9  in which the group K is a CH 2 . 
     
     
       11. The analog of  claim 10  in which the group Z is an OCH 2 . 
     
     
       12. The analog of  claim 11  in which Ar 1  is phenylene. 
     
     
       13. The analog of  claim 12  in which Ar 2  is dichlorophenyl. 
     
     
       14. The analog of  claim 13 , which is:                    
     
     
       15. The analog of  claim 1 , which is: Glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamnino-vancomycin, N-(3-Pyridyl)methyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-Glycyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-L-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or N-D-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or pharmaceutically acceptable salts thereof. 
     
     
       16. The analog of  claim 1 , which is: N-L-Prolyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-8-Alanyl-glucos-6-arnino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-L-Lysyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-L-(3-thiazolyl)alanyl-glucos-6-amino-N-4(3,4-dichlorobenzyloxy)benzyl-vancosamino vancomycin, N-L-(2-thienyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, N-L-Asparagyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or N-D-(3-pyridyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       17. An analog of  claim 3  wherein K and Z are selected from the group consisting of carbonyl, sulfonyl, (C 1-6 )alkylene, (C 1-6 )alkyleneoxy, oxy(C 1-6 )alkylene, (C 1-6 )alkyleneamino, amino(C 1-6 )alkylene, (C 1-3 )alkyleneoxy-(C 1-3 )alkylene, (C 1-6 )alkylenethio, thio(C 1-6 )alkylene, (C 1-6 )alkylenecarbonyl, aminocarbonyl or carbonylamino, (C 1-6 )alkyleneaminocarbonyl, aminocarbonyl(C 1-6 )alkylene, oxy, oxycarbonyl or carbonyloxy, (C 1-6 )alkyleneoxycarbonyl, oxycarbonyl(C 1-6 )alkylene, aminosulfonyl, or sulfonylamino. 
     
     
       18. An analog of  claim 3  wherein Ar 1  and Ar 2  may be the same or different are selected from the group consisting of aromatic or heterocyclic groups, each optionally monosubstituted, disubstituted, or trisubstituted with R 1 ; wherein R 1  can be halo; R 2 ; CN; NO 2 ; CF 3 ; OCH x F (3−x)(x=0−3) ; NHSO 2 R 2 ; OR 2 , SR 2 ; N(R 2 ) 2 ; N + (R 2 ) 3 ; C(O)N(R 2 ) 2 ; SO 2 N(R 2 ) 2 ; heterocyclic; CO 2 R 2 ; C(O)R 2 ; OC(O)R 2 ; NR 2 C(O)R 2 ; or NHC(O)R 2 ; and wherein R 2  independently (where more than one R 2  is present) represents H, aryl, straight or branched (C 1-6 )alkyl, arylalkyl, heterocyclic, heterocyclic(C 1 -C 6 )alkyl, aroyl, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl; and when two R 2  groups are present, they may optionally be linked by one or more covalent bonds to form one or more rings, which may be aromatic, aliphatic, or heterocyclic. 
     
     
       19. An analog according to  claim 1 , wherein the C 6  polar substituent is a group R which has the formula:                    
       in which the groups R 3  and R 4  may be the same or different and selected from the group consisting of H, alkyl, aryl, heterocyclic, aralkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl, aminocarbonyl, substituted arninocarbonyl, substituted oxycarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl, substituted aminosulfonyl, amidino, or substituted amidino, said alkyl, aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, or heterocycliccarbonyl being optionally substituted with 1-3 groups of R 1 ; and wherein R 3  and R 4  may be linked to one another or to one or both of the others by one or more covalent bonds to form one or more aryl or heterocyclic rings of 3-20 members, optionally comprised of C, N, O, or S. 
     
     
       20. An analog of  claim 3  wherein K and Z of K—Ar 1 —Z—Ar 2  are selected from the group consisting of carbonyl, sulfonyl, (C 1-6 )alkylene, (C 1-6 )alkyleneoxy, oxy(C 1-6 )alkylene, (C 1-6 )alkyleneamino, amino(C 1-6 )alkylene, (C 1-3 )alkyleneoxy-(C 1-3 )alkylene, (C 1-6 )alkylenethio, thio(C 1-6 )alkylene, (C 1-6 )alkylenecarbonyl, aminocarbonyl or carbonylamino, (C 1-6 )alkyleneaminocarbonyl, aminocarbonyl(C 1-6 )alkylene, oxy, oxycarbonyl or carbonyloxy, (C 1-6 )alkyleneoxycarbonyl, oxycarbonyl(C 1-6 )alkylene, aminosulfonyl, or sulfonylamino. 
     
     
       21. An analog of  claim 20  wherein Ar 1  and Ar 2  of K—Ar 1 —Z—Ar 2  may be the same or different are selected from the group consisting of aromatic or heterocyclic groups, each optionally monosubstituted, disubstituted, or trisubstituted with R 1 ; wherein R 1  can be halo; R 2 ; CN; NO 2 ; CF 3 ; OCH x F (3−x)(x=0−3) ; NHSO 2 R 2 ; OR 2 , SR 2 ; N(R 2 ) 2 ; N + (R 2 ) 3 ; C(O)N(R 2 ) 2 ; SO 2 N(R 2 ) 2 ; heterocyclic; CO 2 R 2 ; C(O)R 2 ; OC(O)R 2 ; NR 2 C(O)R 2 ; or NHC(O)R 2 ; and wherein R 2  independently (where more than one R 2  is present) represents H, aryl, straight or branched (C 1-6 )alkyl, arylalkyl, heterocyclic, heterocyclic(C 1 -C 6 )alkyl, aroyl, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl; and when two R 2  groups are present, they may optionally be linked by one or more covalent bonds to form one or more rings, which may be aromatic, aliphatic, or heterocyclic. 
     
     
       22. An analog according to  claim 21 , wherein the C 6  polar substituent is a group R which has the formula:                    
       in which the groups R 3  and R 4  may independently be present or absent and, if present, may be the same or different and selected from the group consisting of H, alkyl, aryl, heterocyclic, aralkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl, aminocarbonyl, substituted arninocarbonyl, substituted oxycarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl, substituted aminosulfonyl, amidino, or substituted amidino, said alkyl, aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, or heterocycliccarbonyl being optionally substituted with 1-3 groups of R 1 ; and wherein R 3  and R 4  may be linked to one another or to one or both of the others by one or more covalent bonds to form one or more aryl or heterocyclic rings of 3-20 members, optionally comprised of C, N, O, or S. 
     
     
       23. An analog according to  claim 9 , wherein the group K is (C 1 -C 6 )alkylene oxy and the polar group R is amino. 
     
     
       24. An analog of  claim 15 , which is Glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       25. An analog of  claim 15  which is N-(3-Pyridyl)methyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or pharmaceutically accepable salts thereof. 
     
     
       26. An analog of  claim 15  which is N-Glycyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       27. An analog of  claim 15  which is N-L-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       28. An analog of  claim 15  which is N-D-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       29. An analog of  claim 16  which is N-L-Prolyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or pharmaceutically acceptable salts thereof. 
     
     
       30. An analog of  claim 16  which is N-B-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or pharmaceutically acceptable salts thereof. 
     
     
       31. An analog of  claim 16  which is N-L-Lysyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptable salts thereof. 
     
     
       32. An analog of  claim 16  which is N-L-(3-thiazolyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or pharmaceutically acceptable salts thereof. 
     
     
       33. An analog of  claim 16  which is N-L-Asparagyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or a pharmaceutically acceptable salt thereof. 
     
     
       34. An analog of  claim 16  which is N-L-(2-thienyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or a pharmaceutically acceptable salt thereof. 
     
     
       35. An analog of  claim 16  which is N-D-(3-pyridyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, or a pharmaceutically acceptable salt thereof. 
     
     
       36. An analog according to  claim 3 , wherein K—Ar 1 —Z—Ar 2  is 4-(3,4-dichlorobenzyloxy)benzyl, and R is selected from the group consisting of aminophenylmethylene, phenylmethylene, aminophenylethylene, fluorophenylmethylene, chlorophenylmethylene, methoxyphenylmethylene, 2-piperidylmethylene, methylphenylemethylene, 2-tetrahydrofuranylmethylene, phenylethylene, cyclopentyl, 2-furanomethylene, hydroxyethylene, methyl, n-propyl, allylyl, phenylmethylcarbonyl, and naphthyl. 
     
     
       37. An analog according to  claim 3 , wherein K—Ar 1 —Z—Ar 2  is 4-(3,4-dichlorobenzyloxy)benzyl, and R is selected from the group consisting of chlorobenzyl, 2-hydroxyindanyl, 4-pyridiylmethylene, 2-morpholinomethylene, cyanoethyl, 3,4-dichlorobenzyl, 2-methylpropyl, N-(2-oxazolyl)-n-propyl, 2-(2-hydroxyltetrahydrofuranyl) methyl, azolinyl, 3-thiazofuranyldioxide, cyclopropanyl, 3-amino-N-azolyl, N-piperazinyl, N-piperidinyl, N-morpholino, and N-(4-diaminopiperazinyl). 
     
     
       38. An analog according to  claim 3 , wherein R is NH 2 , K is —CH 2 —, Ar 1  is phenylene, Z is —O—CH 2 —, and Ar 2  is selected from the group consisting of (p-carbonyloxymethylester), phenyl, p-nitrophenyl, p-trifluoromethylphenyl, o-trifluoromethylphenyl, 1-chloro-3-fluorophenyl, and 2-chlorophenyl. 
     
     
       39. An analog according to  claim 3 , wherein R is NH 2 , K is CH 2 , Z is —O—CH 2 —, Ar 2  is 3,4-dichlorophenyl, and Ar 1  is selected from the group consisting of 2-chlorophenylene, 2-methoxyphenylene and 3-methoxyphenylene. 
     
     
       40. An analog according to  claim 3 , wherein R is NH 2 , K is CH 2 , Ar 1  is phenyl, Z is —C(O)—O—, and Ar 2  is p-chlorophenyl or 3,4-dichlorophenyl. 
     
     
       41. An analog of  claim 9 , wherein Ar 2  is 3,4-dichlorophenyl, Z is —OCH 2 —, Ar 1  is phenylene, R is NH 2  and K is selected from the group consisting of —CH 2 —, —C(O)—, —SO 2 —, —CH 2 CH 2 —, —C(O)CH 2 —, —CH 2 C(O)—, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 CH 2 S—, —C(O)O—, —C(O)NH—, and —C(O)N(CH 3 )—. 
     
     
       42. An analog of  claim 9 , wherein R is NH 2 , K is —CH 2 —, Z is —OCH 2 —, Ar 2  is 3,4-dichlorophenyl and Ar 1  is selected from the group consisting of:                  
                   
     
     
       43. An analog according to  claim 9 , wherein R is NH 2 , K is —CH 2 —, Ar 1  is phenylene, Ar 2  is 3,4-dichlorophenylene and Z is selected from the group consisting of —CH 2 —, —C(O)—, —SO 2 —, —S(O)— —S—, —O—, —CH 2 O—, —C=C—, —C=C—, —CH 2 CH 2 CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —C(O)NH—, —C(O)N(CH 3 )—, —SO 2 N(CH 3 )—, —SO 2 NH—, —NHSO 2 —, —N(CH 3 )SO 2 —, —NHC(O)—, —N(CH 3 )C(O)—, —C(O)OCH 2 —, —CH 2 OC(O)—, —CH 2 NHC(O)—, —CH 2 N(CH 3 )CO—, —C(O)N(CH 3 )CH 2 —, —C(O)NHCH 2 —, —SO 2 NHCH 2 —, —SO 2 N(CH 3 )CH 2 —, —CH 2 N(CH 3 )SO 2 —, and —CH 2 NHSO 2 —. 
     
     
       44. An analog according to  claim 9 , wherein R is NH 2 , K is —CH 2 —, Ar 1  is phenylene, Z is —OCH 2 — and Ar 2  is selected from the group consisting of:                  
                 
                   
     
     
       45. An analog according to  claim 9 , wherein K—Ar 1 —Z—Ar 2  is 4-(3,4-dichlorobenzyloxybenzyl) and R is selected from the group consisting of:                  
                 
                 
                   
     
     
       46. A pharmaceutical composition comprising the analog of  claim 1  or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier. 
     
     
       47. A method of treating or preventing a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an effective amount of the analog of  claim 1 .